Neural degeneration invariably accompanies aging, yet some elders are able to maintain excellent cognitive function. The capacity to sustain function in the face of aging and illness is called cognitive reserve. Knowledge of the neural basis underlying cognitive reserve would inform treatment strategies for cognitive decline and dementia. This Mentored Research Scientist Development Award (K01) will provide Dr. Bruce Luber with the necessary training and skills to become an independent investigator with expertise in the neural basis of cognitive reserve, applying innovative tools that may ultimately lead to novel interventions for age related memory loss. Cognitive reserve is thought to be mediated by two mechanisms: (1) resilience of existing neural networks to the effects of aging (neural reserve), and (2) compensation through enlistment of new networks. Functional neuroimaging studies have generated hypotheses regarding the neural basis of these aspects of cognitive reserve, but cannot test causal relationships. This K01 will equip the candidate to test the neural basis of both aspects of cognitive reserve, using image-guided noninvasive brain stimulation. The specific aims are: to identify neural reserve and compensation networks related to working memory in the elderly using fMRI and advanced multivariate analysis comparing young and older adults (Aim 1), and to validate the functional role of neural reserve (Aim 2) and compensation (Aim 3) networks using fMRI-guided TMS. This work extends the candidate's studies showing that fMRI-guided TMS targeted to a reserve network can improve working memory performance at baseline and following sleep deprivation. The career development plan will provide expertise in: 1) the cognitive neuroscience of aging, 2) the clinical use of TMS, 3) the use of fMRI-guided TMS as a neurobiological probe, 4) clinical trial design and statistical analysis, and 5) systems neuroscience. This training and research experience will position Dr. Luber to achieve his long- term goal to translate an advanced understanding of the mechanisms of cognitive reserve into novel tools to study and ultimately to better treat cognitive decline in the elderly. [unreadable] [unreadable] [unreadable]